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Y-T Tai,
Y Landesman,
C Acharya,
Y Calle,
M Y Zhong,
M Cea,
D Tannenbaum,
A Cagnetta,
M Reagan,
A A Munshi, [......],
M Kauffman,
Y Gu,
L Wu,
I Ghobrial,
F Zhan,
A L Kung,
S A Schey,
P Richardson,
N C Munshi, K C Anderson
[show abstract]
[hide abstract]
ABSTRACT: The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that CRM1 is highly expressed in patient MM, plasma cell leukemia cells, and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50 < 200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and NFκB activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory, and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis, and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NFκB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.Leukemia accepted article preview online, 16 April 2013; doi:10.1038/leu.2013.115.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2013; · 8.30 Impact Factor
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C Fernández de Larrea,
R A Kyle,
B G M Durie,
H Ludwig,
S Usmani,
D H Vesole,
R Hajek,
J F San Miguel,
O Sezer,
P Sonneveld, [......],
U-H Mellqvist,
O Landgren,
A Chanan-Khan,
P Moreau,
R Fonseca,
G Merlini,
J J Lahuerta,
J Bladé,
R Z Orlowski,
J J Shah
[show abstract]
[hide abstract]
ABSTRACT: Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (20%) and absolute number (2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.Leukemia advance online publication, 4 January 2013; doi:10.1038/leu.2012.336.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2012; · 8.30 Impact Factor
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N Amodio,
M T Di Martino,
U Foresta,
E Leone,
M Lionetti,
M Leotta,
A M Gullà,
M R Pitari,
F Conforti,
M Rossi, [......],
M Fulciniti,
G Misso,
F Morabito,
M Ferrarini,
A Neri,
M Caraglia,
N C Munshi, K C Anderson,
P Tagliaferri,
P Tassone
[show abstract]
[hide abstract]
ABSTRACT: MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.
Cell Death & Disease 01/2012; 3:e436. · 5.33 Impact Factor
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P G Richardson,
M Delforge,
M Beksac,
P Wen,
J L Jongen,
O Sezer,
E Terpos,
N Munshi,
A Palumbo,
S V Rajkumar, [......],
M-V Mateos,
M Dimopoulos,
S Lonial,
S Jagannath,
J Bladé,
J San Miguel,
G Morgan, K C Anderson,
B G M Durie,
P Sonneveld
[show abstract]
[hide abstract]
ABSTRACT: Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2011; 26(4):595-608. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2011; 26(5):1116-9. · 8.30 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The purpose of these studies was to identify human leukocyte antigen (HLA)-A2(+) immunogenic peptides derived from XBP1 antigens to induce a multiple myeloma (MM)-specific immune response. Six native peptides from non-spliced XBP1 antigen and three native peptides from spliced XBP1 antigen were selected and evaluated for their HLA-A2 specificity. Among them, XBP1(184-192), XBP1 SP(196-204) and XBP1 SP(367-375) peptides showed the highest level of binding affinity, but not stability to HLA-A2 molecules. Novel heteroclitic XBP1 peptides, YISPWILAV or YLFPQLISV, demonstrated a significant improvement in HLA-A2 stability from their native XBP1(184-192) or XBP1 SP(367-375) peptide, respectively. Cytotoxic T lymphocytes generated by repeated stimulation of CD3(+) T cells with each HLA-A2-specific heteroclitic peptide showed an increased percentage of CD8(+) (cytotoxic) and CD69(+)/CD45RO(+) (activated memory) T cells and a lower percentage of CD4(+) (helper) and CD45RA(+)/CCR7(+) (naïve) T cells, which were distinct from the control T cells. Functionally, the cytotoxic T lymphocytes (CTL) demonstrated MM-specific and HLA-A2-restricted proliferation, interferon-γ secretion and cytotoxic activity in response to MM cell lines and importantly, cytotoxicity against primary MM cells. These data demonstrate the distinct immunogenic characteristics of unique heteroclitic XBP1 peptides, which induce MM-specific CTLs and highlights their potential application for immunotherapy to treat the patients with MM or its pre-malignant condition.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2011; 25(10):1610-9. · 8.30 Impact Factor
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S Vallet,
S Pozzi,
K Patel,
N Vaghela,
M T Fulciniti,
P Veiby,
T Hideshima,
L Santo,
D Cirstea,
D T Scadden, K C Anderson,
N Raje
[show abstract]
[hide abstract]
ABSTRACT: Upregulation of cytokines and chemokines is a frequent finding in multiple myeloma (MM). CCL3 (also known as MIP-1α) is a pro-inflammatory chemokine, levels of which in the MM microenvironment correlate with osteolytic lesions and tumor burden. CCL3 and its receptors, CCR1 and CCR5, contribute to the development of bone disease in MM by supporting tumor growth and regulating osteoclast (OC) differentiation. In this study, we identify inhibition of osteoblast (OB) function as an additional pathogenic mechanism in CCL3-induced bone disease. MM-derived and exogenous CCL3 represses mineralization and osteocalcin production by primary human bone marrow stromal cells and HS27A cells. Our results suggest that CCL3 effects on OBs are mediated by ERK activation and subsequent downregulation of the osteogenic transcription factor osterix. CCR1 inhibition reduced ERK phosphorylation and restored both osterix and osteocalcin expression in the presence of CCL3. Finally, treating SCID-hu mice with a small molecule CCR1 inhibitor suggests an upregulation of osteocalcin expression along with OC downregulation. Our results show that CCL3, in addition to its known catabolic activity, reduces bone formation by inhibiting OB function, and therefore contributes to OB/OC uncoupling in MM.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2011; 25(7):1174-81. · 8.30 Impact Factor
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B. C. Potts,
M. X. Albitar, K. C. Anderson,
S. Baritaki,
C. Berkers,
B. Bonavida,
J. Chandra,
D. Chauhan,
J. C. Cusack,
W. Fenical, [......],
Y. Oki,
H. Ovaa,
F. Pajonk,
P. G. Richardson,
A. M. Roccaro,
C. M. Sloss,
M. A. Spear,
E. Valashi,
A. Younes,
M. A. Palladino
[show abstract]
[hide abstract]
ABSTRACT: The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade® ) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid® ), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.
Current Cancer Drug Targets 02/2011; 11(3):254-284. · 4.33 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: LBH589 is a novel pan-histone deacetylase (HDAC) inhibitor that has potent antitumor activity in multiple myeloma and other hematological malignancies. However, its impact on the immune system has not been defined. We here evaluated the effects of LBH589 on human myeloid dendritic cells (DCs) at clinically relevant concentrations. Exposure to LBH589 affected the surface molecule expression on immature and mature DCs, which was associated with DC maturation (CD83↓), antigen presentation (human leukocyte antigen-ABC↓) and T-cell co-stimulation (CD40↓ and CD86↑). LBH589 decreased both protein and polysaccharide antigen uptake capacities by DCs. Importantly, LBH589 impaired DC function to stimulate antigen-specific immune responses, resulting in the significant reduction of invariant natural killer T-cell (CD1d-restricted) and T-cell (major histocompatibility complex-restricted) activation in innate and adaptive immunity. LBH589 also significantly repressed the production of interleukin (IL)-6, IL-10, IL-12p70, IL-23 and tumor necrosis factor-α by Toll-like receptor (TLR)3 and TLR4-induced DC activation, indicating an important role of HDAC activity in immune regulation and inflammation. RelB, a component of the nuclear factor-κ B signaling pathway, was the key component regulated by HDAC inhibition in DCs. Together, our preclinical study demonstrates that LBH589 significantly impairs the phenotype and function of DCs, indicating a need for monitoring the immune status in patients receiving HDAC inhibitor therapy. It also provides a rationale to evaluate LBH589 activity for the treatment of inflammation.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2011; 25(1):161-8. · 8.30 Impact Factor
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T Calimeri,
E Battista,
F Conforti,
P Neri,
M T Di Martino,
M Rossi,
U Foresta,
E Piro,
F Ferrara,
A Amorosi,
N Bahlis, K C Anderson,
N Munshi,
P Tagliaferri,
F Causa,
P Tassone
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2011; 25(4):707-11. · 8.30 Impact Factor
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B C Potts,
M X Albitar, K C Anderson,
S Baritaki,
C Berkers,
B Bonavida,
J Chandra,
D Chauhan,
J C Cusack,
W Fenical, [......],
Y Oki,
H Ovaa,
F Pajonk,
P G Richardson,
A M Roccaro,
C M Sloss,
M A Spear,
E Valashi,
A Younes,
M A Palladino
[show abstract]
[hide abstract]
ABSTRACT: The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.
Current cancer drug targets 01/2011; 11(3):254-84. · 5.13 Impact Factor
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E Terpos,
M A Dimopoulos,
O Sezer,
D Roodman,
N Abildgaard,
R Vescio,
P Tosi,
R Garcia-Sanz,
F Davies,
A Chanan-Khan,
A Palumbo,
P Sonneveld,
M T Drake,
J-L Harousseau, K C Anderson,
B G M Durie
[show abstract]
[hide abstract]
ABSTRACT: Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2010; 24(10):1700-12. · 8.30 Impact Factor
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R A Kyle,
B G M Durie,
S V Rajkumar,
O Landgren,
J Blade,
G Merlini,
N Kröger,
H Einsele,
D H Vesole,
M Dimopoulos, [......],
P Sonneveld,
S Pavlovsky,
A Palumbo,
P G Richardson,
B Barlogie,
P Greipp,
R Vescio,
I Turesson,
J Westin,
M Boccadoro
[show abstract]
[hide abstract]
ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2010; 24(6):1121-7. · 8.30 Impact Factor
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L Santo,
S Vallet,
T Hideshima,
D Cirstea,
H Ikeda,
S Pozzi,
K Patel,
Y Okawa,
G Gorgun,
G Perrone,
E Calabrese,
M Yule,
M Squires,
M Ladetto,
M Boccadoro,
P G Richardson,
N C Munshi, K C Anderson,
N Raje
[show abstract]
[hide abstract]
ABSTRACT: Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3beta knockdown restored MM survival, suggesting the involvement of GSK-3beta in AT7519-induced apoptosis. GSK-3beta activation was independent of RNA pol II dephosphorylation confirmed by alpha-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3beta phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3beta in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM.
Oncogene 04/2010; 29(16):2325-36. · 6.37 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Although outcomes for patients with multiple myeloma (MM) have improved over the past decade, the disease remains incurable and even patients who respond well to induction therapy ultimately relapse and require additional treatment. Conventional chemotherapy and high-dose therapy with stem cell transplantation (SCT) have historically been utilized in the management of relapsed MM, but in recent years the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, have assumed a primary role in this setting. This review focuses on the role of thalidomide, lenalidomide and bortezomib in relapsed and refractory MM, with additional discussion dedicated to emerging drugs in relapsed MM that may prove beneficial to patients with this disease.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2009; 23(12):2222-32. · 8.30 Impact Factor
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A Palumbo,
O Sezer,
R Kyle,
J S Miguel,
R Z Orlowski,
P Moreau,
R Niesvizky,
G Morgan,
R Comenzo,
P Sonneveld, [......],
M Boccadoro,
M Mateos,
W Chen,
H Ludwig,
D Joshua,
J Chim,
V Hungria,
I Turesson,
B G M Durie,
S Lonial
[show abstract]
[hide abstract]
ABSTRACT: In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2009; 23(10):1716-30. · 8.30 Impact Factor
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S Giralt,
E A Stadtmauer,
J L Harousseau,
A Palumbo,
W Bensinger,
R L Comenzo,
S Kumar,
N C Munshi,
A Dispenzieri,
R Kyle, [......],
M Cavo,
D Joshua,
I Turesson,
W Chen,
K Shimizu,
R Powles,
P G Richardson,
R Niesvizky,
S V Rajkumar,
B G M Durie
[show abstract]
[hide abstract]
ABSTRACT: Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2009; 23(10):1904-12. · 8.30 Impact Factor
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G Perrone,
T Hideshima,
H Ikeda,
Y Okawa,
E Calabrese,
G Gorgun,
L Santo,
D Cirstea,
N Raje,
D Chauhan,
M Baccarani,
M Cavo, K C Anderson
[show abstract]
[hide abstract]
ABSTRACT: Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C, at orally achievable concentrations, inhibited in vitro MM cell cytotoxicity of bortezomib and blocked its inhibitory effect on 20S proteasome activity. Specifically, plasma collected from healthy volunteers taking 1 g/day vitamin C reduced bortezomib-induced MM cell death in vitro. This antagonistic effect of vitamin C against proteasome inhibitors is limited to the boronate class of inhibitors (bortezomib and MG262). In vivo activity of this combination treatment was then evaluated using our xenograft model of human MM in SCID (severe combined immune-deficient) mice. Bortezomib (0.1 mg/kg twice a week for 4 weeks) significantly inhibits in vivo MM cell growth, which was blocked by oral vitamin C (40 mg/kg/day). Therefore, our results for the first time show that vitamin C can significantly reduce the activity of bortezomib treatment in vivo; and importantly, suggest that patients receiving treatment with bortezomib should avoid taking vitamin C dietary supplements.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2009; 23(9):1679-86. · 8.30 Impact Factor
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N Raje,
T Hideshima,
S Mukherjee,
M Raab,
S Vallet,
S Chhetri,
D Cirstea,
S Pozzi,
C Mitsiades,
M Rooney, [......],
H Ikeda,
R Carrasco,
P G Richardson,
D Chauhan,
N C Munshi,
S Sharma,
H Parikh,
B Chabner,
D Scadden, K C Anderson
[show abstract]
[hide abstract]
ABSTRACT: Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2009; 23(5):961-70. · 8.30 Impact Factor
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I Breitkreutz,
M S Raab,
S Vallet,
T Hideshima,
N Raje,
C Mitsiades,
D Chauhan,
Y Okawa,
N C Munshi,
P G Richardson, K C Anderson
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2008; 22(10):1973. · 8.30 Impact Factor
